nutrients
Review
Creatine Supplementation and Brain Health
Hamilton Roschel 1, * , Bruno Gualano 1,2 , Sergej M. Ostojic 3






Citation: Roschel, H.; Gualano, B.;
Ostojic, S.M.; Rawson, E.S. Creatine
Supplementation and Brain Health.
Nutrients 2021, 13, 586. https://
doi.org/10.3390/nu13020586
Academic Editor: Richard B. Kreider
Received: 18 January 2021
Accepted: 4 February 2021
Published: 10 February 2021
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Attribution (CC BY) license (https://
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4.0/).
Nutrients 2021, 13, 586. https://doi.org/10.3390/nu13020586
and Eric S. Rawson 4
1 Applied Physiology & Nutrition Research Group, Rheumatology Division, School of Physical Education
and Sport, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo 01246-903, Brazil;
gualano@usp.br
2 Food Research Center, University of São Paulo, Sao Paulo 05508-080, Brazil
3 FSPE Applied Bioenergetics Lab, University of Novi Sad, 21000 Novi Sad, Serbia; sergej.ostojic@chess.edu.rs
4 Department of Health, Nutrition, and Exercise Science, Messiah University, Mechanicsburg, PA 17055, USA;
erawson@messiah.edu
* Correspondence: hars@usp.br; Tel.: +55-11-3061-8789
Abstract: There is a robust and compelling body of evidence supporting the ergogenic and therapeutic
role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms,
there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive
processing, brain function, and recovery from trauma). This is a growing field of research, and
the purpose of this short review is to provide an update on the effects of creatine supplementation
on brain health in humans. There is a potential for creatine supplementation to improve cognitive
processing, especially in conditions characterized by brain creatine deficits, which could be induced
by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine
synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression).
Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined.
Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are
needed. Collectively, data available are promising and future research in the area is warranted.
Keywords: phosphorylcreatine; dietary supplement; cognition; brain injury; concussion
1. Introduction
The ergogenic effects of creatine supplementation are well documented, with evi-
dence supporting its efficacy in increasing muscle strength, lean mass, and exercise perfor-
mance/muscle function, particularly when combined with exercise in different populations,
from athletes to a wide spectrum of patient populations [1–3].
Creatine mechanisms of action involve rapid energy provision by transferring the
N-phosphoryl group from phosphorylcreatine (PCr) to adenosine diphosphate (ADP),
thus resynthesizing adenosine triphosphate (ATP) and spatial energy buffering, transfer-
ring energy from the mitochondria to the cytosol. These mechanisms are responsible for
facilitating ATP homeostasis during high energy turnover, maintaining a low ADP con-
centration and reducing Ca2+ leakage from the sarcoplasmic reticulum and impairment of
force output of the muscle [4–6]. Additionally, creatine could also attenuate the formation
of reactive oxygen species by its coupling with ATP into the mitochondria or by scavenging
radical species in an acellular setting [7]. Its direct and indirect antioxidant effects have
been suggested to have therapeutic effects in neurodegenerative diseases [8].
Although most of the total body’s creatine is found in skeletal muscle, the brain is
also a very metabolically active tissue, accounting for up to 20% of the body’s energy
consumption [9,10]. Creatine kinase (CK), a main enzyme involved in the ATP/CK/PCr
system, is also expressed in a brain-specific isoform (BB-CK) [4–6], suggesting that creatine
may also be relevant for energy provision to the central nervous system (CNS). In fact,
creatine-deficient syndromes involving brain creatine depletion are characterized by major
mental and developmental disorders (e.g., mental retardation, learning delays, autism, and
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Nutrients 2021, 13, x FOR PEER REVIEW 2 of 10

Nutrients 2021, 13, 586 2 of 10

creatine-deficient syndromes involving brain creatine depletion are characterized by ma-
jor mental and developmental disorders (e.g., mental retardation, learning delays, autism,
and seizures), which may be partially reversed by creatine supplementation [11–14]. Cog-
seizures), which may be partially reversed by creatine supplementation [11–14]. Cognitive
nitive processing may also be affected by creatine metabolism, as it may facilitate ATP
processing may also be affected by creatine metabolism, as it may facilitate ATP homeostasis
homeostasis during periods of rapid or altered brain ATP turnover, such as during com-
during periods of rapid or altered brain ATP turnover, such as during complex cognitive
plex cognitive tasks, hypoxia, sleep deprivation, and some neurological conditions
tasks, hypoxia, sleep deprivation, and some neurological conditions [3,15,16]. Additionally,
[3,15,16]. Additionally, creatine supplementation might be beneficial for mild traumatic
creatine supplementation might be beneficial for mild traumatic brain injury (mTBI),
brain injury
which (mTBI),
is also whichwith
associated is also associated
changes withenergy
in brain changesneeds.
in brainThe
energy needs.
effects The ef-
of creatine
fects
supplementation on brain creatine levels, cognitive processing, and mTBI have mTBI
of creatine supplementation on brain creatine levels, cognitive processing, and been
have been reviewed
previously previously reviewed
[3,17,18]. As[3,17,18]. As this field,
this is a growing is a growing field,ofthe
the purpose thispurpose of this
short review is
short review is to provide an update regarding the effects of creatine supplementation
to provide an update regarding the effects of creatine supplementation on brain health in on
brain
humans health in humans
beyond what isbeyond what
discussed is discussed
in Dolan in Dolan et al. [3].
et al. [3].

2. The Effects of Creatine Supplementation on Brain Creatine Levels

While muscle exclusively relies on dietary ingestion and endogenous synthesis from
the liver,
liver, kidneys,
kidneys,and
andpancreas
pancreas[19],
[19],the
thebrain
braincan
cansynthesize
synthesizecreatine.
creatine.TheTheenzymatic
enzymaticap-
paratus
apparatus necessary forfor
necessary endogenous
endogenouscreatine
creatinesynthesis
synthesisisisfound
foundininthe
the nervous
nervous system and
creatine transporters are found at the blood–brain barrier, neurons and oligodendrocytes
cells, indicating that brain creatine may not solely dependent on endogenous production
from other organs or dietary
dietary sources
sources [20].
[20]. Furthermore, brain creatine seems not to be
influenced by habitual dietary intake from food, as similar brain PCr is found found between
between
vegetarians andandomnivores
omnivores[21].[21].Still,
Still, if the
if the intracerebral
intracerebral synthesis
synthesis is limited
is limited due todue to
inher-
inherited disorders of creatine-catalyzing enzyme(s) machinery, dietary
ited disorders of creatine-catalyzing enzyme(s) machinery, dietary provision of the com- provision of the
compound
pound can positively
can positively affectaffect
brainbrain
creatinecreatine concentrations
concentrations [22]. Figure
[22]. Figure 1 illustrates
1 illustrates endog-
endogenous
enous creatine
creatine synthesis
synthesis in thein the brain
brain and itsand its transport
transport acrossacross the blood–brain
the blood–brain barrier.
barrier.

Figure 1. Dietary creatine is transported through the blood–brain barrier via a creatine transporter. Astrocytes cells
can also1.endogenously
Figure produce
Dietary creatine creatine,through
is transported which the
is taken up by the
blood–brain neurons
barrier via a expressing the creatine
creatine transporter. transporter.
Astrocytes Cr:
cells can
creatine; PCr: phosphocreatine;
also endogenously Gly:which
produce creatine, glycine; Arg:up
is taken arginine; AGAT: L-ariginine:
by the neurons expressing theglycine amidinotransferase;
creatine GAA:
transporter. Cr: creatine;
guanidinoacetate; GAMT: guanidinoacetate methyltransferase, SAM: S-adenosylmethionine; CreaT: Cr transporter. Created
with BioRender.com.
Nutrients 2021, 13, 586 3 of 10

Brain creatine content has been suggested to be affected by other factors, such as
aging [23]; however, comparable levels of brain PCr have also been found between ap-
parently healthy elderly and young individuals [24]. Other factors related to aging that
may influence brain creatine concentrations include reduced brain and/or physical activity,
depression, schizophrenia, and panic disorder. The overlap between these factors may be
misleading as to what might be identified as an age-related decline (reviewed in Rawson
and Venezia [25]).
While consistent information is available on supplementation protocols aimed at
increasing muscle creatine content [26], much less is known regarding the optimal sup-
plementation strategy to increase brain creatine levels. A large heterogeneity in respect
to brain creatine assessment technique (i.e., total brain creatine as assessed by H1 -NMR
vs. brain PCr as assessed by P31 -NMR), supplement dose and duration (range 2 to 20 g/d
for 1 to 8 weeks), and population characteristics (including habitual dietary creatine in-
take, health status, etc.) hampers direct comparison between the few studies on the topic.
Further confusion is introduced by the fact that creatine content may differ regionally
within the brain [25,27]. Nevertheless, collectively, the available literature suggests pos-
sible increases in both creatine and PCr in the brain following supplementation, though
smaller than that seen in muscle (~half the increase) [3]. As reviewed in detail by Dolan
et al. [3], there are currently 12 studies of the effects of creatine supplementation on brain
creatine or PCr concentrations. Nine of these studies showed a significant increase in
brain creatine, averaging about 5 to 10%, which is less than the increase in muscle creatine
or PCr resulting from similar supplementation protocols. Some of these studies focused
on patient populations who have altered brain energetics, including females with major
depressive disorder, depression and amphetamine use, and selective serotonin uptake
inhibitor resistant depression. Other groups investigated the effects of creatine ingestion
on brain creatine levels in apparently healthy individuals. There is no clear indication why
a small number of studies were ineffective at increasing brain creatine despite using similar
supplementation protocols, but differences in baseline brain creatine levels, brain creatine
assessment, population characteristics, and dosing strategies likely play a role.
The explanation for these differences in creatine uptake between muscle and brain
remains speculative. As discussed, brain creatine content may rely less on exogenous
creatine than muscle [20,21,24,28], which could theoretically involve a down-regulated
response in brain creatine synthesis upon supplementation. Alternative to this hypothesis
is the demonstration that the brain lacks the expression of creatine transporter in the
astrocytes involved in the blood–brain barrier, thus implying a limited permeability of
the brain to the circulating creatine [29], which is in line with the lack of increase in
brain creatine following supplementation reported by some studies [24,28,30]. It is also
plausible to speculate that if the brain is, in fact, resistant to exogenous creatine, a high-
dose, long duration protocol would be needed, such as those used in the study by Dechent
et al. [27] (i.e., 20 g/day for 4 weeks). The need for a higher supplementation dose in
order to increase brain creatine level, as compared to the supplementation dose required
for muscle, is further corroborated by data available from the only study assessing both
muscle and brain creatine levels in response to supplementation, with increases found in
the former, but not the latter [24]. Of interest, supplementing guanidinoacetic acid (GAA),
a creatine precursor, was found superior to an equimolar dose of creatine in increasing
brain creatine content [31]. While creatine is mainly transported via a specific transporter
(SLC6A8 or CT1; also used for GAA transport), dietary GAA could be imported to the
brain through additional delivery transporters and routes (including SLC6A6, GAT2, and
passive diffusion) [32] and become readily available for methylation to creatine. Although
preliminary, these data are of relevance considering the inherent capacity of the brain to
synthesize creatine and its theoretical impaired ability to transport creatine through the
blood–brain barrier, thus warranting further research on alternative strategies to increase
brain creatine.
Nutrients 2021, 13, 586
Table 1. Effects of creatine supplementation on cognitive performance.
Creatine Supplementation
Population
20 g/day + 5 g/day for
Healthy older women
Semiprofessional,
non-vegetarian, male
mountain bikers
Healthy young women
(vegetarian and
meat-eaters)
Professional male rugby
0.05 or 0.1 g/kg/bw for
players who were
sleep-deprived (3–5 h)
20 g/day for 5 days +
Healthy young adults
Healthy young men and
women
Healthy young men and
women who were
sleep-deprived (24 h)
Healthy elderly men and
women
Healthy young men who
were sleep-deprived (36 h)
4 of 10
3. Creatine Supplementation and Cognition
The interest in the effects of creatine supplementation on cognition is not new. Despite
the number of positive studies available on the subject (Summarized in Table 1), differences
between investigations including study populations, cognitive function testing, and supple-
mentation dosing and duration precludes direct comparison; however, some conclusions
can be made. Although controversial [28,33,34], creatine supplementation may positively
influence some aspects of cognition in different experimental paradigms [10,35–40]. Im-
portantly, its effects seem more pronounced in stressful conditions such as hypoxia [8]
and sleep deprivation combined with exercise [10,37,38]. Despite the suggestion that more
complex or demanding cognitive processes are more prone to respond to supplementation
(as they are more energy demanding), inconsistencies regarding cognitive test response to
supplementation hampers further conclusions [37,38]), which may be attributed to differ-
ences in experimental design such as the sleep deprivation period and exercise intensity
employed between studies.
Cognitive Tests (CT)
Reference
Protocol Outcomes (O)
CT: Mini-mental state examination, stroop, trail making,
digit span, delay recall test and the short version of the Alves et al. (2013)
24 weeks geriatric depression scale [33]
O: No change
CT: Simple and choice reaction time, differentiation task
test, Eiksen flanker test and Corsi block test Borchio et al. (2020)
20 g/day for 7 days
O: Creatine increased performance in choice reaction time, [41]
Eiksen flanker test and Corsi block test.
CT: Word recall, simple and choice reaction time, rapid
visual information processing and controlled oral word
association test
Benton and Donohoe
20 g/day for 5 days O: Word recall test performance was reduced in meat-eater
(2011) [15]
after creatine supplementation (within-group comparison).
Post supplementation performance was higher in
vegetarians than in meat-eaters.
CT: Rugby passing skill test
O: Sleep deprivation reduced passing accuracy and
Cook et al. (2011) [42]
1 day creatine reversed this effect (trend for greater effect with
larger dose).
CT: Backward digit span test and ravens advanced
progressive matrices. Hammett et al. (2010)
5 g/day for 2 days O: Backward digit span performance was increased after [35]
creatine.
CT: Memory scanning, number-pair matching, sustained
attention, arrow flankers and IQ test
5 g/day for 15 days Ling et al. (2009) [36]
O: Aspect of improvement was reported in all the cognitive
tests performed in the creatine group.
CT: Random number generation, forward and backward
recall, visual reaction time, static balance and mood state
McMorris et al. (2006)
20 g/day for 7 days O: Performance reduction was attenuated in the creatine
[38]
group for random movement generation, choice reaction
time, balance and mood.
CT: Random number generation, forward and backward
recall and long-term memory tests
McMorris et al.
20 g/day for 7 days O: Forward number recall, forward and backward spatial
(2007a) [16]
recall and long-term memory performance were enhanced
after creatine supplementation.
CT: Random number generation, short-term number recall,
visual reaction time, cognitive effort, dynamic balance test
McMorris et al.
20 g/day for 7 days and mood state
(2007b) [37]
O: Performance on the random number generation test was
improved following creatine.
Nutrients 2021, 13, 586
Creatine Supplementation
Population
Healthy male and female
0.3 g/kg/day for 7 days
children
Vegan and vegetarian
healthy male and female
young adults
Healthy male and female
0.03 g/kg/day for 6 weeks
young adults
Male and female
institutionalized older
adults (with full physical
and mental capacities
preserved)
Healthy male and female
young adults exposed to
experimental hypoxia
Healthy male and female
young adults exposed to
mental fatigue (90 min
Stoop task)
Healthy male and female
young adults
5 of 10
Table 1. Cont.
Cognitive Tests (CT)
Reference
Protocol Outcomes (O)
CT: Stroop, Rey auditory verbal learning test, Raven
Merege-Filho et al.
progressive matrices and trail making test
(2017) [28]
O: No change
CT: Ravens advanced progressive matrices and Wechsler
auditory backward digit span task Rae and Broer (2015)
5 g/day for 6 weeks
O: Creatine improved performance on the Raven’s test and [17]
the backward digit span task.
CT: Automated neuropsychological assessment metrics Rawson et al. (2008)
O: No change [34]
CT: Montreal Cognitive Assessment (MoCA) questionnaire
Smolarek et al. (2020)
5 g/day for 16 weeks O: Creatine (plus resistance training) improved MoCA
[43]
scores.
CT: Neuropsychological test comprising verbal and visual
memory, finger tapping, symbol digit coding stroop test,
test of shifting attention, continuous performance test, Turner et al. (2015)
20 g/day for 7 days
alertness and peripheral and corticomotor excitability [10]
O: Creatine supplementation offset hypoxia-induced
decrements in a number of cognitive tests.
CT: Psychomotor performance (visuomotor task with
Fitlight-hardware and software), strength endurance task,
Flanker test, heart rate, blood glucose, success motivation
and intrinsic motivation, mood, session ratings of
Van Cutsem et al.
20 g/day for 7 days perceived exertion and mental fatigue
(2020) [44]
O: Accuracy throughout the 90 min Stroop task and
strength endurance (in the non-dominant hand) were
improved with creatine. No other effects of creatine
supplementation were observed.
CT: Serial calculation task (Uchida-Kraeplin)
O: Both groups increased mean performance. Mental Watanabe et al. (2002)
8 g/day for 5 days
fatigue, assessed during the second half of the test, was [40]
increased in the creatine group only.
In elderly individuals, specifically, literature is conflicting on the effects of creatine
supplementation on cognitive performance. While McMorris et al. [16] showed improved
cognitive performance, Alves et al. [33] found creatine (alone or associated with exercise
training) ineffective. Both studies are limited by the lack of brain creatine concentration
assessments, casting doubt on whether aging-related reduction in cognitive processing
may arise from the presence of, for instance, neurodegenerative diseases or whether the
supplementation protocol employed (designed for increasing muscle creatine content) may
have been insufficient to significantly increase brain PCr. Recently, Smolarek et al. [43]
found increased cognitive performance (and handgrip strength) after a 16 week interven-
tion combining resistance training and creatine supplementation (5 g/day) in a pilot study
including older adults. The results are, however, limited by the absence of an exercising
control group and inconsistent cognitive performance in the control group across time,
thus hampering further conclusion on the effects of supplementation alone.
It has been contended that vegetarians may differentially respond to creatine sup-
plementation when compared to meat-eaters. In this respect, cognitive function has been
shown to be improved in vegetarians after creatine supplementation [39]. Another study
found greater effects on memory in vegetarians as compared to omnivores following crea-
tine supplementation [15]. Importantly, the lack of a control group (meat-eaters) and the
fact that between-group differences were due to decreased performance in the omnivores,
rather than an improvement in the vegetarians, limits the conclusions of this study. Addi-
tionally, comparable brain creatine concentrations have been shown between meat-eaters
and vegetarians [21], which undermines the theory that vegetarians should respond better
Nutrients 2021, 13, 586 6 of 10

than meat-eaters due to lower pre-supplementation brain creatine. More research should be
conducted on the differential responses to creatine supplementation between vegetarians
and omnivores.
Improvements in cognitive processing capability is also of interest to athletes. Several
sports include motor control, decision making, coordination, reaction time, and other
cognitive tasks as key aspects of performance, which may be affected by mental fatigue [45].
In this respect, creatine may play an ergogenic role, as, theoretically, it may mitigate
mental fatigue, thus favouring performance. Indeed, creatine has been shown effective in
attenuating the effects of sleep deprivation on throwing accuracy in rugby players [42],
while no effect was observed on passing accuracy in non-stressed soccer players [46,47].
Brain creatine content was not assessed in these studies, raising uncertainty as to whether
the results observed result from changes in brain creatine. Nonetheless, the discrepancy in
the results may, at least partially, relate to the suggestion that creatine supplementation is
most effective under stressed cognitive processes conditions such as sleep deprivation.
More recently, two studies revisited the subject, with interesting results. Borchio
et al. [41] found improved performance in selected indexes of cognitive function after
a time-trial track test in semi-professional mountain bikers supplemented with creatine.
Interestingly, no prior cognitive deficit-inducing condition, such as sleep deprivation, was
imposed, suggesting that creatine could potentially attenuate mental fatigue even in non-
stressed situations. Van Cutsem et al. [44] studied the effects of creatine supplementation
on mental fatigue and its negative effects on psychomotor skills in a non-athlete population
and found that creatine was able to improve Stroop accuracy during a 90 min Stroop
task and to increase strength endurance (assessed by a handgrip strength test) pre-to-post
Stroop task. Importantly, no effects of supplementation were observed on the mental-
fatigue-induced impairments in psychomotor and cognitive performance. Collectively,
although these results suggest a potential role of creatine on mental fatigue, whether and
to what extent this could affect specific sports performance remains to be elucidated.

4. Creatine Supplementation and Brain Injury, Concussion, and Hypoxia

One of the characteristics of traumatic brain injury is the alteration of ATP demand due
to reduced blood flow and hypoxia [48]. Importantly, brain creatine is reduced following a
mild traumatic brain injury (mTBI) [49], making creatine supplementation, and subsequent
increase in brain creatine, a potentially valuable strategy to reduce severity of, or enhance
recovery from, mTBI or concussion by offsetting negative changes in energy status. The
duration of the dysregulation in brain energy metabolism is not clearly defined, but could
remain for weeks if not years. Alosco et al. [50] reported on retired players from the National
Football League (aged 40 to 69) who had experienced repetitive head impacts during
their career and many years later had complaints of cognitive and/or behavioral/mood
symptoms. In this cohort, there was a relationship between greater exposure to repetitive
head impacts and decreased brain creatine in the parietal white matter. This indicates that
there could be later-life derangements in brain energy metabolism subsequent to mTBI, and
lends support to the concept that creatine supplementation could be valuable in enhancing
recovery from mTBI, even years after the injury. In addition to its potential role in aiding
the cellular energy crisis induced by injury, creatine may lessen other features of mTBI,
such as membrane disruption leading to calcium influx, nerve damage, mitochondrial
dysfunction, oxidative stress, and inflammation (reviewed in [48,51]).
In an experimental model mimicking the effects of mTBI, Turner et al. [10] found
that supplementation was able to increase brain creatine and cognitive processing during
oxygen deprivation. Animal models have also been employed to investigate the effects of
creatine supplementation on traumatic brain injury. Sullivan et al. [52] found significant
reduction in brain damage following traumatic brain injury in both mice (36%) and rats
(50%). These large effects are compelling, but as humans only increase brain creatine
about 10% in response to supplementation and some animals increase brain creatine 30
to 50%, it is difficult to generalize these data to the general population or athletes [53].
Nutrients 2021, 13, 586 7 of 10

Despite its potential, experimental data in humans are still scarce; however, results from
the few studies available are promising. Creatine supplementation has been shown able to
improve cognition, communication, self-care, personality, and behavior, and reductions in
headaches, dizziness, and fatigue in children with mTBI [54,55].
Collectively, despite limited data, creatine supplementation seems potentially benefi-
cial in reducing severity of or enhancing recovery from mTBI, warranting further studies
on its role not only as a post-injury therapy but also as a neuroprotective agent in popula-
tions at high risk of mTBI. As has been described elsewhere, creatine supplements have
documented muscular performance benefits, are inexpensive, widely available, and have
a strong safety profile [26,56–63]. Encouraging supplementation to reduce damage from
or enhance recovery from mTBI based primarily on animal and theoretical data in lieu
of clinical trials would ordinarily be considered premature. However, in this instance,
given the devastating effects of mTBI, combined with the large body of safety and efficacy
creatine supplementation data, encouraging supplementation for populations who are at
high risk for mTBI might be considered more prudent.

5. Conclusions and Future Directions

There is a potential for creatine supplementation to improve cognitive processing,
especially in conditions characterized by brain creatine deficits, which could be induced
by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g.,
creatine synthesis enzyme deficiencies, mTBI, aging, Alzheimer’s disease, depression).
However, at least three main gaps remain. First, it is important to determine the
optimal creatine protocol able to increase brain creatine levels. So far, dose-response
studies are lacking and protocols are heterogenous. Second, supplementation studies
concomitantly assessing brain creatine levels and cognitive function are needed, as it may
help establish causation for the effect of creatine supplementation on cognition. Third, the
identification of novel conditions in which creatine supplementation may be more effective
in improving cognitive function is warranted as creatine in a rested healthy brain has been
shown to have a lessened effect.

Author Contributions: Conceptualization, H.R., B.G., S.M.O. and E.S.R.; writing—review and
editing, H.R., B.G., S.M.O., E.S.R. All authors have read and agreed to the published version of the
manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors would like to thank all of the research participants, scholars, and
funding agencies who have contributed to the research cited in this manuscript. The figure was
created with BioRender.com.
Conflicts of Interest: B.G. has received research grants, creatine donation for scientific studies, travel
support for participation in scientific conferences and honorarium for speaking at lectures from
AlzChem (a company which manufactures creatine). Additionally, he serves as a member of the
Scientific Advisory Board for Alzchem. E.S.R. has conducted industry-sponsored research on creatine
and received financial support for presenting on creatine at industry-sponsored scientific conferences.
Additionally, he serves as a member of the Scientific Advisory Board for AlzChem, who sponsored
this special issue. S.M.O. serves as a member of the Scientific Advisory Board on creatine in health and
medicine (AlzChem LLC). S.M.O. owns patent “Sports Supplements Based on Liquid Creatine” at
the European Patent Office (WO2019150323 A1), and active patent application “Synergistic Creatine”
at the UK Intellectual Property Office (GB2012773.4). S.M.O. has served as a speaker at Abbott
Nutrition, a consultant of Allied Beverages Adriatic and IMLEK, and an advisory board member
for the University of Novi Sad School of Medicine, and has received research funding related to
creatine from the Serbian Ministry of Education, Science, and Technological Development, Provincial
Secretariat for Higher Education and Scientific Research, AlzChem GmbH, KW Pfannenschmidt
GmbH, and ThermoLife International LLC. S.M.O. is an employee of the University of Novi Sad and
does not own stocks and shares in any organization.
Nutrients 2021, 13, 586 8 of 10

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